Title

Author

Date of Award

Document Type

Thesis

Degree Name

Master of Science (MS)

Program

Biomedical Sciences

Track

Neuroscience

Research Advisor

Steven J. Tavalin, Ph.D.

Committee

Alejandro M. Dopico, Ph.D.
Matthew Ennis, Ph.D.

Abstract

L-proline is a non-essential amino acid and one of the major amino acid constituents of extracellular fluid. Specific mutations in genes that control proline metabolism lead to hyperprolinemia which is characterized by an increase in the level of blood and cerebrospinal fluid concentration of l-proline. In fact, deletion or mutation of the PRODH gene which codes for proline oxidase (POX) / proline dehydrogenase which is critical for proline metabolism leads to Type I hyperprolinemia and is strongly associated with schizophrenia, autism and mental retardation. Proline has previously been shown to be a low affinity agonist at glutamate and glycine receptors. Because schizophrenia is thought to arise from glutamate receptor hypofunction and l-proline can act at glutamate receptors, it is necessary to understand whether increase in l-proline can contribute to glutamate receptor hypofunction.

The aim of this research was to determine the pharmacological profile of physiological and pathophysiological relevant concentrations of l-proline at two recombinant AMPA receptors: homomeric GluR1 and heteromeric GluR1/2. Dose response to l-proline (concentrations of 3 µM – 10 mM) at homomeric GluR1 and heteromeric GluR1/2 receptors were determined and compared to saturating concentration of glutamate (10 mM). The effect of tonically present physiological (3 µM) or pathophysiological (30 µM) levels of l-proline on glutamate-evoked responses at both receptor types were also determined. This research supports previous findings that l-proline is a low affinity agonist at glutamate receptors activating less than 5 % of current elicited by a saturating concentration of glutamate (10 mM). Tonically present pathophysiological concentration of l-proline was observed to lead to a decrease in glutamate activation of homomeric GluR1 but not heteromeric GluR1/2 receptors. This decrease in glutamate-induced current was blocked by the application of 0.1 mM cyclothiazide indicating that at pathophysiological concentrations l-proline leads to selective desensitization of GluR1 receptors. These actions of l-proline may be relevant for understanding how hyperprolinemia contributes to glutamate receptor hypofunction in schizophrenia.